Several publications are referenced in this application by author name and year of journal publication in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
It is known that hyperlipidemia is a significant risk factor in the development of cardiovascular disease (CVD). Hyperlipidemia is a condition marked by an increase in serum levels of one or both of serum cholesterol and neutral fats, primarily triglycerides (TG). Research conducted over the last several decades has established that elevated serum TG levels constitute an independent risk factor for CVD. Accordingly, the development of agents for reducing or controlling serum TG levels has received considerable attention as a means of preventing or delaying the onset of CVD.
As a dietary treatment for hypertriglyceridemia, polyunsaturated fatty acids (PUFAs) have been recommended, in conjunction with limited caloric intake. In this connection, dietary marine oils have been shown to exhibit very potent hypotriglyceridemic (TG lowering) properties, especially in type V hypertriglyceridemic individuals (Roche, 1999; Harris 1999; Harris 1989).
Numerous studies have now shown that the daily consumption of fish oils containing as little as 2–4 grams of n-3 PUFAs can significantly decrease circulating TG levels in both normolipidemic and hypertriglyceridemic individuals (Harris 1989; Harris 1997). Although there has been some question regarding the constituent(s) of dietary marine oils that is (are) responsible for this hypotriglyceridemic effect, both eicosapentaenoic acid (20:5 n-3) (EPA) and docosahexaenoic acid (22:6 n-3) (DHA), which are major constituents of fish oils, have been shown to possess this hypotriglyceridemic activity in humans (Weber 1999; Agren, 1996). However, this effect is not a general attribute of the n-3 PUFAs, as oils containing dietary alpha-linolenic acid (18:3 n-3) (ALA), a precursor of EPA and DHA, have little if any hypotriglyceridemic activity even when consumed in oils delivering as much as 20 grams of ALA per day (Kelley 1993; Abbey, 1990). A hypotriglyceridemic effect has been reported for ALA-containing oils when consumed at extremely elevated concentrations (40–60 grams ALA/day) (Singer, 1990), but this effect compares poorly to that of dietary marine oils and may be a generalized effect of high doses of dietary PUFAs, since high doses of linoleic acid have similar properties. However, the dietary use of marine oils as hypotriglyceridemic agents is undesirable for many individuals due to their generally unpleasant taste and odor. Furthermore, many studies investigating the potential benefits of marine oil consumption report associated gastrointestinal problems such as bloating and gas.
There have been few reports on studies in humans to determine the extent to which consumption of stearidonic acid (SDA) influence in vivo conversion to longer chain fatty acids, i.e., Arachidonic acid and Docosapentaenoic acid (DPA). Those that have been published appear inconclusive. For example, no increase in longer chain n-3 fatty acids was seen in test subjects who consumed the daily dose of 0.65 g ALA and 0.17 g SDA (Wu, 1999). Intensive care unit patients who were administered the equivalent of 5.7 g ALA and 0.7 g SDA per day were found to have a 20% increase in the EPA content of red blood cell membranes that was statistically significant (Diboune, 1992). Measurement of plasma fatty acids in a similar group of patients showed a significant increase in DPA; however, there is no mention of the plasma content of the of EPA (Diboune, 1993).
Another fatty acid that can be found in some less common dietary-oils is gamma-linolenic acid (18:3 n-6) (GLA). Although oils containing GLA, such as Borage oil and Evening Primrose oil (EPO), have been extensively studied for their anti-inflammatory benefits, very little information exists regarding their effects on circulating TG levels. Five studies have been reported in humans in which circulating TGs were monitored following the consumption of oils containing GLA. In all five studies, human diets were supplemented with EPO. Three of the studies showed no effect of the supplementation on circulating TG levels in subjects consuming 0.3 grams, 0.6 grams and 2.7 grams of GLA per day for up to 4 months (Ishikawa, 1989; Abraham, 1990; Viikari 1986). The Abraham study (2.7 grams/day) utilized healthy males without signs of hyperlipidemia, but who were selected based on their being in the lowest quintile for GLA content in adipose tissue biopsies from a larger group of subjects. The Ishikawa study (0.3 grams GLA/day) involved 19 hypercholesterolemic patients. Ten patients did not have associated hypertriglyceridemia and nine were considered hypertriglyceridemic based on a cut off of 150 mg/dl. The Viikari study (0.6 grams GLA/day) utilized hyperlipidemic patients. The two other studies reported chat diets supplemented with EPO, delivering either 0.24 grams GLA/day or 2 grams GLA/day, significantly decreased circulating TG levels by 48% and 35%, respectively (Guivernau, 1994; Chaintreuil, 1984). In the Chaintreuil study, all subjects were diabetics taking daily subcutaneous insulin injections. The subjects were grouped to receive either 2 grams GLA/day or 0.5 grams GLA/day. The 2.0 grams/day group were found to have a decrease in plasma TG of 35% while the 0.5 grams/day showed no change in TG levels. The Guivernau paper studied 12 hyperlipidemic men who received 0.24 grams GLA/day. These men had combined hyperlipidemia and any subjects who were taking lipid lowering drugs discontinued the treatment at least 8 weeks before the start of the study. The oil supplement was reported to cause a 48% decrease in plasma TG within a 4 week period, and those individuals with the highest initial levels showed the most marked decrease.
While EPO and Borage Oil are distinctive, in part, because they contain GLA, there have been no reported studies to date which have addressed whether GLA is the active component responsible for the hypotriglyceridemic effects reported in the last-mentioned two studies. Therefore, in view of the inconsistent reports in the literature and the absence of studies addressing whether GLA itself may possess hypotriglyceridemic activity, there is at this time no conclusive evidence to indicate that dietary GLA possesses hypotriglyceridemic properties.
Known pharmaceutical agents for treating hypertriglyceridemia include the class of fibrate drugs, e.g., clofibrate, benzafibrate and gemfibrozil, as well as nicotinic acid and derivatives thereof. Nicotinic acid has been shown to be safe and effective for lowering serum TG levels, but the therapeutic dosage must be worked up to gradually to minimize the flushing and itching of skin which frequently cannot be tolerated by the patient. Clinically relevant interactions of fibrates with other anti-hyperlipidemic drugs include rhabdomyolysis when used in combination with HMG CoA-reductase inhibitors (statins), and decreased bioavailability when combined with certain bile acid sequesterants (Farmer and Gotto, 1994). Also, potentiation of the anticoagulant effects of coumarin may cause bleeding (Blum, 1992).
From the foregoing summary, it will be appreciated that a need exists for a composition for treating hypertriglyceridemia that is both effective and well tolerated by patients to whom it is administrated.